Upregulation of NR4A3 increases sensitivity to niraparib in ovarian cancer cells resistant to this drug

IF 2.2 4区生物学 Q3 CELL BIOLOGY

Journal of Molecular Histology Pub Date : 2025-09-30 DOI:10.1007/s10735-025-10490-8

Jianwei Wang, Yu Wei, Benjun Chen

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Abstract

Acquired resistance is the major clinical change for patients with ovarian cancer undergoing niraparib (NRP) treatment. Targeting NRP-resistant cells would be NRP offers an effective strategy for reversing resistance and inhibiting disease progression. NR4A3 is known as a tumor suppressor in multiple cancers, but its role in NRP resistance of ovarian cancer is still unclear. NRP-resistant ovarian cancer cell lines (A2780/NRP and OVCAR3/NRP) were established by gradually increasing NRP concentrations. The phenotype of resistant cell lines was characterized using proliferation, colony formation, and migration assays. RNA sequencing was performed to identify genes dysregulated in the resistant cell lines. We also performed gain- and loss-of-function assays to investigate the role of NR4A3 in NRP resistance. The resistance indices for A2780/NRP and OVCAR3/NRP were 8.95 and 4.42, respectively. These resistant cells exhibited slower proliferation and robust colony formation and migration abilities. NR4A3 exhibited the highest average log2 fold change among the candidates. Overexpression of NR4A3 sensitized the NRP-resistant cells and reduced their proliferation, colony formation, and migration capabilities, whereas downregulation of NR4A3 in the parental cells caused opposite results. Downregulation of NR4A3 contributes to NRP resistance, and activation of NR4A3 maybe a promising strategy to reverse NRP resistance.

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NR4A3的上调增加了耐药卵巢癌细胞对尼拉帕尼的敏感性。

获得性耐药是卵巢癌患者接受尼拉帕尼（NRP）治疗的主要临床变化。NRP为逆转耐药和抑制疾病进展提供了有效的策略。NR4A3在多种癌症中被认为是肿瘤抑制因子，但其在卵巢癌NRP耐药中的作用尚不清楚。通过逐渐增加NRP浓度，建立了耐NRP卵巢癌细胞系A2780/NRP和OVCAR3/NRP。抗性细胞系的表型通过增殖、菌落形成和迁移测定来表征。RNA测序鉴定耐药细胞系中基因失调。我们还进行了功能增益和功能丧失分析，以研究NR4A3在NRP耐药中的作用。A2780/NRP和OVCAR3/NRP的抗性指数分别为8.95和4.42。这些抗性细胞表现出较慢的增殖和强大的集落形成和迁移能力。NR4A3表现出最高的平均log2倍变化。NR4A3的过表达使nrp抗性细胞增敏，降低其增殖、集落形成和迁移能力，而NR4A3在亲本细胞中的下调则产生相反的结果。NR4A3的下调有助于NRP耐药，激活NR4A3可能是逆转NRP耐药的一种有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Molecular Histology 生物-细胞生物学

CiteScore

5.90

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： The Journal of Molecular Histology publishes results of original research on the localization and expression of molecules in animal cells, tissues and organs. Coverage includes studies describing novel cellular or ultrastructural distributions of molecules which provide insight into biochemical or physiological function, development, histologic structure and disease processes. Major research themes of particular interest include: - Cell-Cell and Cell-Matrix Interactions; - Connective Tissues; - Development and Disease; - Neuroscience. Please note that the Journal of Molecular Histology does not consider manuscripts dealing with the application of immunological or other probes on non-standard laboratory animal models unless the results are clearly of significant and general biological importance. The Journal of Molecular Histology publishes full-length original research papers, review articles, short communications and letters to the editors. All manuscripts are typically reviewed by two independent referees. The Journal of Molecular Histology is a continuation of The Histochemical Journal.